EAU 2018: Results of POUT – A Phase III Randomized Trial of Peri-Operative Chemotherapy Versus Surveillance in Upper Tract Urothelial Cancer

Copenhagen, Denmark (UroToday.com) Alison Birtle, MD presented results of the POUT trial. Given that the role of post nephroureterectomy treatment for upper tract urothelial carcinoma (UTUC) is unclear, the UK led POUT trial (CRUK/11/027; NCT01993979) addressed whether adjuvant chemotherapy improves disease free survival (DFS) for patients with histologically confirmed pT2-T4 N0-3 M0 UTUC.

For this trial, patients (maximum n=345) that had a WHO performance status 0-1, and were ≤90 days post nephroureterectomy were randomized (1:1) to 4 cycles of gemcitabine-cisplatin (gemcitabine-carboplatin if GFR 30-49ml/min) or surveillance with chemotherapy given on recurrence, if required. The primary endpoint was DFS, and patients had cross-sectional imaging and cystoscopy every 6 months for the first 2 years, then annually to 5 years. Toxicity was assessed by CTCAE v4. The trial was powered to detect a hazard ratio (HR) of 0.65 (i.e. improvement in 3-year DFS from 40% to 55%; 2-sided alpha=5%, 80% power) with Peto-Haybittle (p<0.001) early stopping rules for efficacy and inefficacy. Secondary endpoints included metastasis-free survival, overall survival, toxicity (CTCAE v4) and patient-reported quality of life, assessed by EORTC QLQ-C30 and EQ5D.

There were 248 patients included in the trial between May 31, 2015, and September 5, 2017, including 123 patients randomized to surveillance and 125 to chemotherapy at 57 UK centers. In October 2017, the independent trial oversight committees recommended POUT close to recruitment as data collected to date (data snapshot 5th September 2017) met the early stopping rule for efficacy. At the time of interim analysis, median follow-up was 17.6 months (IQR 7.5-33.6). Patients were a median 69 years of age (range 36-88), 30% had pT2 disease, 65% pT3, and 91% pN0. Grade ≥3 toxicities were reported in 60% chemotherapy patients and 24% surveillance patients. During the treatment period, the most common grade ≥3 [≥4] toxicities in chemotherapy patients were neutropenia 29% [5%] (vs. 0% surveillance) and thrombocytopenia 7% [6%] (vs. 0%). There were 47 (38.2%) DFS events in the surveillance cohort and 29 (23.2%) in the chemotherapy cohort; the unadjusted HR was 0.47 (95%CI 0.29-0.74) in favor of chemotherapy (log-rank p= 0.0009). Two-year DFS was 51% for surveillance (95%CI 39-61) and 70% for chemotherapy (95%CI 58-79). Metastasis-free survival also favored chemotherapy, with a HR of 0.49 (95%CI 0.30-0.79, p=0.003).

Dr. Birtle and her colleagues concluded that adjuvant chemotherapy is tolerable, and improved metastasis-free survival in UTUC. Recruitment to the POUT trial was terminated early because of efficacy favoring the chemotherapy arm, however, follow-up for overall survival continues. POUT is the largest randomized trial in UTUC and its results support the use of adjuvant chemotherapy as a new standard of care.

Presented by: Alison Birtle, MD, Royal Preston Hospital, Preston, United Kingdom

Co-Authors: Johnson M, Kockelbergh R, Keeley F, Catto J, Bryan R, Chester J, Jones R, Hill M, Donovan J, French A, Harris C, Powles T, Todd R, Tregellas L, Wilson C, Winterbottom A, Lewis R, Hall E

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, twitter: @zklaassen_md at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark

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